Nearly all the functions of the liver display zonation in distribution within each the lobule. Hepatic cortisol availability is controlled by enzymes that regenerate cortisol from inactive cortisone (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1). Dysregulation of hepatic 11β-HSD1 activity has been implicated in insulin resistance. Key processes such as gluconeogenesis are located in the periportal hepatocytes, although current dogma describes hepatic 11β-HSD1 to show strong pericentral zonation.
11β-HSD1 immunohistochemistry and laser capture microdissection studies for mRNA expression on normal human liver samples showed strong pericentral staining and variable degrees of periportal staining in different samples. It was speculated that this may be related to hepatic energy state.
Male C57BL/6 mice age 10 weeks (6 per group) had livers harvested after timed fast of 0, 2, 4, 8 and 12 h, and refed for 12 h following a 12 h fast. 11β-HSD1 protein expression was increased throughout the liver parenchyma as well in pericentral areas, in addition to intense periportal staining of hepatic 11β-HSD1 in the fasted mice. Periportal expression was minimal in livers from fed and refed mice.
This zonation of 11β-HSD1 expression is entirely novel but may account for some of the known actions of GC in the liver. This may account for some of the known actions of GC in the liver. Periportal cortisol generation during fasting would promote metabolic processes including gluconeogenesis. Conversely, in the fed state, pericentral cortisol generation would promote pericentral metabolic functions including lipogenesis. This strongly implicates hepatic 11β-HSD1 in the regulation of key hepatic metabolic functions in health, with of course the possibility of dysregulation having impact upon metabolic disease states including insulin resistance and diabetes mellitus. At a molecular level, dynamic hepatic 11β-HSD1 expression has key implications upon the regulation of hepatic ER nutrient signalling. These concepts represent a significant paradigm shift in the thus far understood role and expression of hepatic 11β-HSD1.